There is an enzyme in the brain that plays a key role in sensing and controlling levels of glucose in the blood. The underlying mechanism that it triggers appears to link to both type 1 and type 2 diabetes, according to US researchers, who suggest the discovery could lead to new treatments for diabetes.
They report how they discovered the part played by the enzyme – known as prolyl endopeptidase (PREP) – in the Proceedings of the National Academies of Sciences (PNAS).
There are two types of diabetes. Type 1 is where the body’s ability to make insulin – an enzyme that helps cells convert glucose into energy – is impaired due to loss of insulin-producing cells in the pancreas. Type 2 arises not through lack of insulin, but because cells lose their ability to use it properly and become insulin-resistant.
The study found PREP links to both types of diabetes – one way involves communication with the pancreas, and the other way involves sensing levels of glucose in the blood.
Lead author Sabrina Diano, a professor in the Departments of Obstetrics, Gynecology & Reproductive Sciences, Comparative Medicine, and Neurobiology at Yale University School of Medicine, New Haven, CT, says they discovered that PREP – found in a part of the hypothalamus known as the ventromedial nucleus – triggers a series of steps that control glucose in the blood.
The team already knew that the ventromedial nucleus has brain cells that are capable of sensing glucose, and wanted to find out more about the link to PREP.
They discovered that PREP gives brain cells in this part of the brain the ability to sense glucose. When the cells detect rising glucose levels, they instruct the pancreas to secrete more insulin, which keeps glucose in check and prevents diabetes.
When they genetically engineered mice with low levels of the enzyme, they found the mice had high levels of blood glucose and developed diabetes.
They confirmed the effect of reduced PREP by treating normal mice with a PREP inhibitor. The mice showed decreased insulin levels and impaired glucose tolerance.
And when they restored PREP function in the mice bred to have low PREP – by injecting them with a virus that causes the relevant gene to be switched on again – they found it reversed the glucose intolerance the mice had shown before.
Prof. Diano says the low levels of enzyme prevented the neurons from sensing increased levels of blood glucose, which in turn meant they could not control release of insulin from the pancreas, which led the mice to become glucose intolerant and diabetic.
She and her colleagues conclude that:
“Taken together, our results unmask a previously unknown player in central regulation of glucose metabolism and pancreatic function.”
If they find the targets in the enzyme that make the neurons sense changes in glucose levels, then the researchers believe it could lead to a new type of drug to regulate insulin secretion. Such a drug could not only treat type 2 diabetes, but perhaps even prevent it, says Prof. Diano.
Funds from the National Institutes of Health and the American Diabetes Association helped to finance the study.
Meanwhile, another recently published study from China found that shift work may increase risk for type 2 diabetes, particularly in men. While the researchers who carried out the meta-analysis did not examine why the risk is higher in men, they suggest it could be that repeated disruption of the body’s internal clock affects levels of testosterone in men. Other studies have shown low levels of the male hormone are linked to insulin resistance and diabetes.